Therapeutic uses of glucokinase activators in combination with insulin or insulin analogs

ABSTRACT

Methods of using glucokinase (GK) activators are generally disclosed herein, particularly in combination with insulin or insulin analogs. In certain aspects, the disclosure provides methods of treating type 1 diabetes that include administering a GK activator in combination with insulin or insulin analogs. Uses of GK activators as a medicament are also disclosed herein, as well as the manufacture of a medicament for such uses.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2019/036227, filed Jun. 10, 2019, which claims benefit of U.S.Provisional Application Nos. 62/683,772, filed Jun. 12, 2018, and62/857,753, filed Jun. 5, 2019.

TECHNICAL FIELD

Methods of using glucokinase (GK) activators are generally disclosedherein, particularly in combination with insulin or insulin analogs. Incertain aspects, the disclosure provides methods of treating type 1diabetes that include administering a GK activator in combination withinsulin or insulin analogs. In certain other aspects, the disclosureprovides methods of treating related conditions and improving glycemiccontrol, such as increasing the percentage of time a subject is intarget blood-glucose range, decreasing the percentage of time a subjectis in hypoglycemic or hyperglycemic range, reducing body weight,reducing glycated hemoglobin levels, reducing the occurrence ofketoacidosis, lowering mean daily blood-glucose levels, reducing totaldaily bolus insulin dose, reducing total daily basal insulin dose,reducing total daily insulin dose, reducing total number of dailyinsulin injections, reducing total number of daily basal insulininjections, reducing total number of bolus insulin injections, reducingtotal daily bolus insulin dose at each meal, reducing number ofhypoglycemic events over a period of time, reducing number of severehypoglycemic events over a period of time. Uses of GK activators as amedicament are also disclosed herein, as well as the manufacture of amedicament for such uses.

BACKGROUND

Diabetes mellitus type 1 (type 1 diabetes) is a chronic condition thatresults from the autoimmune destruction of the insulin-producing betacells in the pancreas. As a result, persons suffering from type 1diabetes cannot produce sufficient insulin to permit them to regulateblood-glucose levels properly. Thus, without treatment, they wouldlikely suffer from acute conditions resulting from extremely highblood-glucose. But, even with treatment, persons suffering from type 1diabetes can still experience fluctuations in blood-glucose levels thatresult in acute conditions (such as hyperglycemia and hypoglycemia) andthat can eventually increase risk of chronic conditions, such as heartdisease, stroke, blindness (due to diabetic retinopathy), kidneyfailure, and poor blood circulation to the limbs (which can result inthe need to amputate limbs that no longer benefit from sufficientcirculation).

Type 1 diabetes can generally only be managed through the administrationof insulin or insulin analogs. Recent decades have witnessed anexpansion in the different kinds of insulin that is available, includingrapid-acting insulin, short-acting insulin, intermediate-acting insulin,and long-acting insulin. Further, devices have recently come to marketthat offer continuous glucose monitoring, coupled with a pump for makingreal-time adjustments to insulin dosing. Many pharmaceutical drugtherapies useful for treating non-insulin dependent diabetes have shownlow or no effectiveness at treating type 1 diabetes. That is becausemany pharmaceutical drug therapies rely on the body's ability to makeendogenous insulin. Thus, such therapies are of little use in treatingtype 1 diabetes, because type 1 diabetics have little or no ability tomake and secrete endogenous insulin.

Thus, there is a continuing need to develop effective pharmaceuticalcompounds that can assist in the management of type 1 diabetes withoutrelying on the production of endogenous insulin.

SUMMARY

The present disclosure generally provides methods of treating type 1diabetes and related conditions using combinations of a liver-selectiveglucokinase (GK) activator and insulin or analogs thereof. It wassurprisingly discovered that activation of GK in the liver GK (versus GKin the pancreas or brain) could improve efficacy of insulin therapy,improve glycemic control and/or simplify treatment regimens in type 1diabetics. Therefore, it was discovered that one could achieve theseresults, in certain respects, by coupling insulin administration withadministration of a liver-selective GK activator.

Glucokinase (GK) is an enzyme that, among other things, facilitatesphosphorylation of glucose to glucose-6-phosphate. In vertebrates,GK-mediated glucose phosphorylation typically occurs in cells in theliver, pancreas, gut, and brain. In each of these organs, GK can play arole in regulating carbohydrate metabolism by acting as a glucosesensor, triggering shifts in metabolism or cell function in response torising and/or falling levels of blood glucose. Small-molecule GKactivators are useful because they can enhance the rate of glucosephosphorylation, and thereby reduce the amount of glucose in the blood.

Methods of Treatment

In a first aspect, the disclosure provides methods of treating type 1diabetes, the methods comprising administering to a subject in needthereof a liver-selective glucokinase activator in combination withinsulin or an analog thereof. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of increasing thepercentage of time in target blood-glucose range in a subject havingtype 1 diabetes, the methods comprising administering to a subject inneed thereof a liver-selective glucokinase activator in combination withinsulin or an analog thereof. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing the totaldaily bolus insulin dose in a subject having type 1 diabetes, themethods comprising administering to a subject in need thereof aliver-selective glucokinase activator in combination with insulin or ananalog thereof. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of lowering meandaily blood-glucose in a subject having type 1 diabetes, the methodscomprising administering to a subject in need thereof a liver-selectiveglucokinase activator in combination with insulin or an analog thereof.In some embodiments thereof, the liver-selective glucokinase activatoris{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing bloodglucagon levels in a subject having type 1 diabetes, the methodscomprising administering to a subject in need thereof a liver-selectiveglucokinase activator in combination with insulin or an analog thereof.In some embodiments thereof, the liver-selective glucokinase activatoris{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of lowering glycatedhemoglobin levels in a subject having type 1 diabetes, the methodscomprising administering to a subject in need thereof a liver-selectiveglucokinase activator in combination with insulin or an analog thereof.In some embodiments thereof, the liver-selective glucokinase activatoris{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing thepercentage of time in hypoglycemic range in a subject having type 1diabetes, the methods comprising administering to a subject in needthereof a liver-selective glucokinase activator in combination withinsulin or an analog thereof. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing thepercentage of time in hyperglycemic range in a subject having type 1diabetes, the methods comprising administering to a subject in needthereof a liver-selective glucokinase activator in combination withinsulin or an analog thereof. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing theincidence, duration, or likelihood of diabetic ketoacidosis in a subjecthaving type 1 diabetes, the methods comprising administering to asubject in need thereof a liver-selective glucokinase activator incombination with insulin or an analog thereof. In some embodimentsthereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing theincidence, duration, or likelihood of diabetic ketosis in a subjecthaving type 1 diabetes, the methods comprising administering to asubject in need thereof a liver-selective glucokinase activator incombination with insulin or an analog thereof. In some embodimentsthereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing one ormore metabolic ketones in a subject having type 1 diabetes, the methodscomprising administering to a subject in need thereof a liver-selectiveglucokinase activator in combination with insulin or an analog thereof.In some embodiments thereof, the liver-selective glucokinase activatoris{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing bodyweight in a subject having type 1 diabetes, the methods comprisingadministering to a subject in need thereof a liver-selective glucokinaseactivator in combination with insulin or an analog thereof. In someembodiments thereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing totaldaily basal insulin dose in a subject having type 1 diabetes, themethods comprising administering to a subject in need thereof aliver-selective glucokinase activator in combination with insulin or ananalog thereof. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing totaldaily insulin dose in a subject having type 1 diabetes, the methodscomprising administering to a subject in need thereof a liver-selectiveglucokinase activator in combination with insulin or an analog thereof.In some embodiments thereof, the liver-selective glucokinase activatoris{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing the totalnumber of daily insulin injections in a subject having type 1 diabetes,the methods comprising administering to a subject in need thereof aliver-selective glucokinase activator in combination with insulin or ananalog thereof. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing totalnumber of daily basal insulin injections in a subject having type 1diabetes, the methods comprising administering to a subject in needthereof a liver-selective glucokinase activator in combination withinsulin or an analog thereof. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing the totalnumber of daily bolus insulin injections in a subject having type 1diabetes, the methods comprising administering to a subject in needthereof a liver-selective glucokinase activator in combination withinsulin or an analog thereof. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing totaldaily bolus insulin dose at each meal in a subject having type 1diabetes, the methods comprising administering to a subject in needthereof a liver-selective glucokinase activator in combination withinsulin or an analog thereof. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing thenumber of hypoglycemic events over a period of time in a subject havingtype 1 diabetes, the methods comprising administering to a subject inneed thereof a liver-selective glucokinase activator in combination withinsulin or an analog thereof. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of reducing thenumber of severe hypoglycemic events over a period of time in a subjecthaving type 1 diabetes, the methods comprising administering to asubject in need thereof a liver-selective glucokinase activator incombination with insulin or an analog thereof. In some embodimentsthereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides methods of treatment toachieve any of the previous improvements in glycemic control (such asreducing time in hypoglycemic range or reduction in number ofhypoglycemic or severe hypoglycemic events) in combination with eitherno decrease in level of HbA1c in the subject or only a slight increase(0.1%, 0.2%, or 0.3%) in HbA1c in a subject having type 1 diabetes, themethods comprising administering to a subject in need thereof aliver-selective glucokinase activator in combination with insulin or ananalog thereof. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

Uses of Combination

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor treating type 1 diabetes. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor increasing the percentage of time in target blood-glucose range in asubject having type 1 diabetes. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing total daily bolus insulin dose in a subject having type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor lowering mean daily blood-glucose in a subject having type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing blood-glucagon levels in a subject having type 1 diabetes.In some embodiments thereof, the liver-selective glucokinase activatoris{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor lowering glycated hemoglobin levels in a subject having type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing the percentage of time in hypoglycemic range in a subjecthaving type 1 diabetes. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing the percentage of time in hyperglycemic range in a subjecthaving type 1 diabetes. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing the incidence, duration, or likelihood of diabeticketoacidosis in a subject having type 1 diabetes. In some embodimentsthereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing the incidence, duration, or likelihood of diabetic ketosisin a subject having type 1 diabetes. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing one or more metabolic ketones in a subject having type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing body weight in a subject having type 1 diabetes. In someembodiments thereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing total daily basal insulin dose in a subject having type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing total daily insulin dose in a subject having type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing the total number of daily insulin injections in a subjecthaving type 1 diabetes. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing the total number of daily basal insulin injections in asubject having type 1 diabetes. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing the total number of daily bolus insulin injections in asubject having type 1 diabetes. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing total daily bolus insulin dose at each meal in a subjecthaving type 1 diabetes. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing the number of hypoglycemic events over a period of time ina subject having type 1 diabetes. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereoffor reducing the number of severe hypoglycemic events over a period oftime in a subject having type 1 diabetes. In some embodiments thereof,the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in combination with insulin or an analog thereofto achieve any of the previous improvements in glycemic control, such asreducing time in hypoglycemic or reduction in number of hypoglycemic orsevere hypoglycemic events) in combination with either no decrease inlevel of HbA1c in the subject or only a slight increase in HbA1c in asubject having type 1 diabetes, the methods comprising administering toa subject in need thereof a liver-selective glucokinase activator incombination with insulin or an analog thereof. In some embodimentsthereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

Manufacture of a Medicament

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for treating type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for increasing thepercentage of time in target blood-glucose range in a subject havingtype 1 diabetes. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing total dailybolus insulin dose in a subject having type 1 diabetes. In someembodiments thereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for lowering mean dailyblood-glucose in a subject having type 1 diabetes. In some embodimentsthereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducingblood-glucagon levels in a subject having type 1 diabetes. In someembodiments thereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for lowering glycatedhemoglobin levels in a subject having type 1 diabetes. In someembodiments thereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing thepercentage of time in hypoglycemic range in a subject having type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing thepercentage of time in hyperglycemic range in a subject having type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing theincidence, duration, or likelihood of diabetic ketoacidosis in a subjecthaving type 1 diabetes. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing theincidence, duration, or likelihood of diabetic ketosis in a subjecthaving type 1 diabetes. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing one or moremetabolic ketones in a subject having type 1 diabetes. In someembodiments thereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing body weightin a subject having type 1 diabetes. In some embodiments thereof, theliver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing total dailybasal insulin dose in a subject having type 1 diabetes. In someembodiments thereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing total dailyinsulin dose in a subject having type 1 diabetes. In some embodimentsthereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing the totalnumber of daily insulin injections in a subject having type 1 diabetes.In some embodiments thereof, the liver-selective glucokinase activatoris{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing total numberof daily basal insulin injections in a subject having type 1 diabetes.In some embodiments thereof, the liver-selective glucokinase activatoris{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing the totalnumber of daily bolus insulin injections in a subject having type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing total dailybolus insulin dose at each meal in a subject having type 1 diabetes. Insome embodiments thereof, the liver-selective glucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing the number ofhypoglycemic events over a period of time in a subject having type 1diabetes. In some embodiments thereof, the liver-selective glucokinaseactivator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof for reducing the number ofsevere hypoglycemic events over a period of time in a subject havingtype 1 diabetes. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

In another aspect, the disclosure provides uses of a liver-selectiveglucokinase activator in the manufacture of a medicament for use incombination with insulin or an analog thereof to achieve any of theprevious improvements in glycemic control (such as reducing time inhypoglycemic range or reduction in number of hypoglycemic or severehypoglycemic events) in combination with either no decrease in level ofHbA1c in the subject or only a slight increase in HbA1c in a subjecthaving type 1 diabetes. In some embodiments thereof, the liver-selectiveglucokinase activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

Other aspects and embodiments are set forth in the foregoing drawings,detailed description, and claims.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 displays the percentage of time each subject's blood glucoselevel was between 70 and 180 mg/dL at each dose (400, 800, and 1200mg/day of UT-1) and for baseline, where each data point represents themedian of four days (days 3-6) at each dose for each subject.

FIG. 2 displays the percentage of time each subject's blood glucoselevel was between 54 and 70 mg/dL at each dose (400, 800, and 1200mg/day of UT-1) and for baseline, where each data point represents themedian of four days (days 3-6) at each dose for each subject.

FIG. 3 displays the percentage of time each subject's blood glucoselevel was less than 54 mg/dL at each dose (400, 800, and 1200 mg/day ofUT-1) and for baseline, where each data point represents the median offour days (days 3-6) at each dose for each subject.

FIG. 4 displays the percentage of time each subject's blood glucoselevel was greater than 180 mg/dL at each dose (400, 800, and 1200 mg/dayof UT-1) and for baseline, where each data point represents the medianof four days (days 3-6) at each dose for each subject.

FIG. 5 displays the mean bolus insulin dose (U) per day at each dose(400, 800, and 1200 mg/day of UT-1) and for baseline, where each datapoint represents the mean of four days (days 3-6) at each dose for eachsubject.

FIG. 6 displays the mean basal insulin dose (U) per day at each dose(400, 800, and 1200 mg/day of UT-1) and for baseline, where each datapoint represents the mean of four days (days 3-6) at each dose for eachsubject.

DETAILED DESCRIPTION

The following description recites various aspects and embodiments of theinventions disclosed herein. No particular embodiment is intended todefine the scope of the invention. Rather, the embodiments providenon-limiting examples of various compositions, and methods that areincluded within the scope of the claimed inventions. The description isto be read from the perspective of one of ordinary skill in the art.Therefore, information that is well known to the ordinarily skilledartisan is not necessarily included.

Definitions

The following terms and phrases have the meanings indicated below,unless otherwise provided herein. This disclosure may employ other termsand phrases not expressly defined herein. Such other terms and phrasesshall have the meanings that they would possess within the context ofthis disclosure to those of ordinary skill in the art. In someinstances, a term or phrase may be defined in the singular or plural. Insuch instances, it is understood that any term in the singular mayinclude its plural counterpart and vice versa, unless expresslyindicated to the contrary.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. For example,reference to “a substituent” encompasses a single substituent as well astwo or more substituents, and the like.

As used herein, “for example,” “for instance,” “such as,” or “including”are meant to introduce examples that further clarify more generalsubject matter. Unless otherwise expressly indicated, such examples areprovided only as an aid for understanding embodiments illustrated in thepresent disclosure, and are not meant to be limiting in any fashion. Nordo these phrases indicate any kind of preference for the disclosedembodiment.

As used herein, “administer” or “administering” means to introduce, suchas to introduce to a subject a compound or composition. The term is notlimited to any specific mode of delivery, and can include, for example,subcutaneous delivery, intravenous delivery, intramuscular delivery,intracisternal delivery, delivery by infusion techniques, transdermaldelivery, oral delivery, nasal delivery, and rectal delivery.Furthermore, depending on the mode of delivery, the administering can becarried out by various individuals, including, for example, ahealth-care professional (e.g., physician, nurse, etc.), a pharmacist,or the subject (e.g., self-administration).

As used herein, “treat” or “treating” or “treatment” can refer to one ormore of: delaying the progress of a disease, disorder, or condition;controlling a disease, disorder, or condition; ameliorating one or moresymptoms characteristic of a disease, disorder, or condition; ordelaying the recurrence of a disease, disorder, or condition, orcharacteristic symptoms thereof, depending on the nature of the disease,disorder, or condition and its characteristic symptoms.

As used herein, “subject” refers to any mammal such as, but not limitedto, humans, horses, cows, sheep, pigs, mice, rats, dogs, cats, andprimates such as chimpanzees, gorillas, and rhesus monkeys. In someembodiments, the “subject” is a human. In some such embodiments, the“subject” is a human who exhibits one or more symptoms characteristic ofa disease, disorder, or condition. The term “subject” does not requireone to have any particular status with respect to a hospital, clinic, orresearch facility (e.g., as an admitted patient, a study participant, orthe like).

As used herein, the terms “blood glucose level”, “blood sugar level”,“plasma glucose level” and “blood sugar concentration” refer to theamount of glucose present in the blood of a subject, and these terms maybe used interchangeably. Blood glucose levels are typically measured inunits of mg/dL or mmol/L.

As used herein, the term “metabolic ketone” refers to any compoundproduced by metabolization of fatty acids, such as by liver enzymes, andincludes, but is not limited to, acetoacetate (AcAc),beta-hydroxybutyrate (BHB), and acetone.

As used herein, the term “hypoglycemia” refers to a blood glucose levelbelow a normal level for a subject. In a human, hypoglycemia may bedefined as a blood glucose level of less than 70 mg/dL. In anembodiment, hypoglycemia in a human is a blood glucose level of lessthan 70 mg/dL and greater than or equal to 54 mg/dL.

As used herein, the term “severe hypoglycemia” refers to a blood glucoselevel significantly below a normal level for a subject. In a human,severe hypoglycemia may be defined as a blood glucose level of less than54 mg/dL.

As used herein, the term “hypoglycemic event” refers to a blood glucoselevel below normal level for a subject for a period of time. In anembodiment, a hypoglycemic event may occur upon a single measure ofblood glucose level below normal through self-monitoring blood glucose(SMBG). In other embodiments, where blood glucose levels arecontinuously monitored, a hypoglycemic event may occur over a period oftime such as where the blood glucose level is continuously below normalfor at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120minutes. In an embodiment, in a human a hypoglycemic event may bedefined as a blood glucose level of less than 70 mg/dL for a period oftime or a single SMBG measurement. In another embodiment, in a human ahypoglycemic event may be defined as a blood glucose level of less than70 mg/dL and greater than or equal to 54 mg/dL for a period of time or asingle SMBG measurement. The end of the hypoglycemic event may occurafter a subject's blood glucose level continuously rises above athreshold for a period of time. For example, blood glucose level mayneed to be continuously above a threshold for at least 1, 2, 3, 4, 5, 6,7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes to mark the end of ahypoglycemic event. In an embodiment, in a human the end of ahypoglycemic event may be defined as a blood glucose level of greaterthan 70 mg/dL for a period of time or a single SMBG measurement.

As used herein, the term “severe hypoglycemic event” refers to a bloodglucose level significantly below a normal level for a subject for aperiod of time. In an embodiment, a severe hypoglycemic event may occurupon a single measure of blood glucose level significantly below normalthrough self-monitoring blood glucose (SMBG). In other embodiments,where blood glucose levels are continuously monitored, a severehypoglycemic event may occur over a period of time such as where theblood glucose level is continuously below normal for at least 1, 2, 3,4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes. In anembodiment, in a human a severe hypoglycemic event may be defined as ablood glucose level of less than 54 mg/dL for a period of time or asingle SMBG measurement. The end of the severe hypoglycemic event mayoccur after a subject's blood glucose level continuously rises above athreshold for a period of time or a single SMBG measurement. Forexample, blood glucose level may need to be continuously above athreshold for at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30,60, or 120 minutes to mark the end of a hypoglycemic event. In anembodiment, in a human the end of a severe hypoglycemic event may bedefined as a blood glucose level of greater than or equal to 54 mg/dLfor a period of time or a single SMBG measurement.

As used herein, the term “hyperglycemia” refers to a blood glucose levelabove the normal level in a subject. In a human, hyperglycemia may bedefined as a blood glucose level of greater than 180 mg/dL. In anembodiment, hyperglycemia in a human is a blood glucose level of greaterthan 180 mg/dL and less than or equal to 250 mg/dL.

As used herein, the term “severe hyperglycemia” refers to a bloodglucose level significantly above the normal level in a subject. In ahuman, severe hyperglycemia may be defined as a blood glucose level ofgreater than 250 mg/dL.

As used herein, the term “hyperglycemic event” refers to a blood glucoselevel above normal level for a subject for a period of time. In anembodiment, a hyperglycemic event may occur upon a single measure ofblood glucose level above normal through self-monitoring blood glucose(SMBG). In other embodiments, where blood glucose levels arecontinuously monitored, a hyperglycemic event may occur over a period oftime such as where the blood glucose level is continuously above normalfor at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120minutes. In an embodiment, in a human a hyperglycemic event may bedefined as a blood glucose level of greater than 180 mg/dL for a periodof time or a single SMBG measurement. In another embodiment, in a humana hyperglycemic event may be defined as a blood glucose level of greaterthan 180 mg/dL and less than or equal to 250 mg/dL for a period of timeor a single SMBG measurement. The end of the hyperglycemic event mayoccur after a subject's blood glucose level continuously falls below athreshold for a period of time. For example, blood glucose level mayneed to be continuously below a threshold for at least 1, 2, 3, 4, 5, 6,7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes to mark the end of ahyperglycemic event. In an embodiment, in a human the end of ahyperglycemic event may be defined as a blood glucose level of less than180 mg/dL for a period of time or a single SMBG measurement.

As used herein, the term “severe hyperglycemic event” refers to a bloodglucose level significantly above a normal level for a subject for aperiod of time. In an embodiment, a severe hyperglycemic event may occurupon a single measure of blood glucose level significantly above normalthrough self-monitoring blood glucose (SMBG). In other embodiments,where blood glucose levels are continuously monitored, a severehyperglycemic event may occur over a period of time such as where theblood glucose level is continuously above normal for at least 1, 2, 3,4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30, 60, or 120 minutes. In anembodiment, in a human a severe hyperglycemic event may be defined as ablood glucose level of greater than 250 mg/dL for a period of time or asingle SMBG measurement. The end of the severe hyperglycemic event mayoccur after a subject's blood glucose level continuously falls below athreshold for a period of time or a single SMBG measurement. Forexample, blood glucose level may need to be continuously below athreshold for at least 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 15, 20, 25, 30,60, or 120 minutes to mark the end of a hyperglycemic event. In anembodiment, in a human the end of a severe hyperglycemic event may bedefined as a blood glucose level of less than or equal to 250 mg/dL fora period of time or a single SMBG measurement.

As used herein, the term “bolus insulin dose” is an insulin dose that isspecifically administered in a subject immediately before or immediatelyafter or around meal times to keep blood glucose levels under controlfollowing a meal. A bolus insulin dose should act quickly and soshort-acting insulin, rapid-acting insulin, or combinations thereof areoften used in bolus insulin doses.

As used herein, the term “basal insulin dose” is an insulin dose that isadministered to a subject to keep blood glucose levels within acceptableranges during period of fasting such as between meals or during periodsof sleeping. A basal insulin dose is often administered once or twice aday, but may be administered more often. Basal insulin doses need to actover a relatively long period of time (such as several hours) andtherefore a basal insulin dose often comprises a long-acting insulin, anintermediate-acting, or a mixture of a long-acting andintermediate-acting insulin.

As used herein, the term “baseline” refers to a period prior treatmentand the associated level or value of an item being measured during thatpre-treatment period. In an embodiment, the pre-treatment period may bea continuous period 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, ormore before treatment. The pre-treatment period may end immediatelybefore treatment begins or the pre-treatment period may be a continuousperiod that ends at least 1 day, 2 days, 3 days or more before treatmentbegins.

As used herein, the term “pharmaceutical composition” is used to denotea composition that may be administered to a mammalian host, e.g.,orally, topically, parenterally, by inhalation spray, or rectally, inunit dosage formulations containing conventional non-toxic carriers,diluents, adjuvants, vehicles and the like. The term “parenteral” asused herein, includes subcutaneous injections, intravenous,intramuscular, intracisternal injection, or by infusion techniques.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt of a compound which are generally prepared by reacting the freebase with a suitable organic or inorganic acid or by reacting the acidwith a suitable organic or inorganic base. Representative salts includethe following salts: acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate,carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, potassium, salicylate, sodium, stearate, subacetate,succinate, tannate, tartrate, teoclate, tosylate, triethiodide,trimethylammonium, and valerate. When an acidic substituent is present,such as —COOH, there can be formed the ammonium, morpholinium, sodium,potassium, barium, calcium salt, and the like, for use as the dosageform. When a basic group is present, such as amino or a basic heteroarylradical, such as pyridyl, there can be formed an acidic salt, such ashydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate,trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate,succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate,methanesulfonate, ethanesulfonate, picrate, and the like. In certainembodiments, the GK activator is in the form of hydrochloride acid salt.In other embodiments, the GK activator is in the form of a free acid.

As used herein, the unit term “mg/kg” refers to the mass (measured inmg) of compound administered to a subject per the mass (measured in kg)of the subject. For example, “administering 1.0 mg/kg daily to asubject” refers to administering 170 mg daily to a subject having a massof 170 kg.

As used herein, “mix” or “mixed” or “mixture” refers broadly to anycombining of two or more compositions. The two or more compositions neednot have the same physical state; thus, solids can be “mixed” withliquids, e.g., to form a slurry, suspension, or solution. Further, theseterms do not require any degree of homogeneity or uniformity ofcomposition. This, such “mixtures” can be homogeneous or heterogeneous,or can be uniform or non-uniform. Further, the terms do not require theuse of any particular equipment to carry out the mixing, such as anindustrial mixer.

As used herein, “optionally” means that the subsequently describedevent(s) may or may not occur. In some embodiments, the optional eventdoes not occur. In some other embodiments, the optional event does occurone or more times.

As used herein, “comprise” or “comprises” or “comprising” or “comprisedof” refer to groups that are open, meaning that the group can includeadditional members in addition to those expressly recited. For example,the phrase, “comprises A” means that A must be present, but that othermembers can be present too. The terms “include,” “have,” and “composedof” and their grammatical variants have the same meaning. In contrast,“consist of” or “consists of” or “consisting of” refer to groups thatare closed. For example, the phrase “consists of A” means that A andonly A is present.

As used herein, “or” is to be given its broadest reasonableinterpretation, and is not to be limited to an either/or construction.Thus, the phrase “comprising A or B” means that A can be present and notB, or that B is present and not A, or that A and B are both present.Further, if A, for example, defines a class that can have multiplemembers, e.g., A₁ and A₂, then one or more members of the class can bepresent concurrently.

As used herein, a “GK activator” is a compound that activates GK in asubject, such as a human, in direct or indirect response to the presenceof the compound, or a metabolite thereof, in the subject. WO 2005/066145provides a non-limiting list of compounds that are GK activators.Further, GK activators may activate GK wherever GK is present, but somemay selectively activate GK in certain systems or organs. For thetreatment of reduction of blood glucose levels, one is generallyconcerned with GK activation in the pancreas and/or the liver. Where aGK activator is a liver-selective GK activator, the GK activatordirectly or indirectly increases glucose utilization in the liver(hepatic cells) at doses that do not induce a substantial increase ininsulin secretion by the pancreas (beta-cells) in response to glucose(e.g., less than a 25% increase, or less than a 15% increase, or lessthan a 10% increase, or less than a 5% increase, or less than a 3%increase in insulin secretion by the pancreas in response to glucose) orthat do not induce a substantial increase in GK activity in othersystems or organs such the brain or CNS. In some embodiments, theliver-selective GK activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.

Other terms are defined in other portions of this description, eventhough not included in this subsection.

Combinations of GK Activators and Insulin

In one or more of the aforementioned aspects, the disclosure providesmethods of administering GK activators (or, in some embodiments,liver-selective GK activators) to subjects in need thereof. In general,such methods include administering to a subject in need thereof a GKactivator in combination with insulin or an analog thereof.

Any suitable GK activator or liver-selective GK activator can be used.In some embodiments, the liver-selective GK activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof. In some furtherembodiments, the liver-selective GK activator is{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid. In some other embodiments, the liver-selective GK activator is apharmaceutically acceptable salt of{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid.

The GK activator can be administered in any suitable way, includingsubcutaneous delivery, intravenous delivery, intramuscular delivery,intracisternal delivery, delivery by infusion techniques, transdermaldelivery, oral delivery, nasal delivery, and rectal delivery. In someembodiments of any of the aforementioned embodiments, the administeringcomprises orally administering the liver-selective GK activator.Suitable oral dosage forms are described in further detail below.

The liver-selective GK activator is administered in combination withinsulin or an analog thereof. In this context, “in combination with”does not necessarily imply that the agents are administered on the sameschedule or as part of a common dosage form. In some instances, thesemedications may be once-daily or once-weekly medications, and may beadministered by different means.

Insulin

The insulin or analog thereof may be administered in any suitable means,including, but not limited to, oral administration (via gut or lungs),subcutaneous administration (such as continuous subcutaneous insulininfusion), administration by injection. In some further embodiments, theinsulin or analog thereof is administered by subcutaneousadministration, or administration by injection. In another embodiment,insulin or analog thereof is administered by two different routes.

Any suitable form of insulin or its analogs can be used. These include,but are not limited to, rapid-acting insulin, regular- or short-actinginsulin, intermediate-acting insulin, and long-acting insulin. Wheninjected subcutaneously, rapid-acting insulin generally reaches theblood stream about 15 minutes after injection and is effective for 2 to4 hours. Types of rapid-acting insulin include: Insulin glulisine(Apidra), insulin lispro (Humalog), and insulin aspart (NovoLog). Wheninjected subcutaneously, regular- or short-acting insulin generallyreach the bloodstream within 30 minutes after injection and is effectivefor approximately 3 to 6 hours. Types of regular- or short actinginsulin included: Humulin R, Novolin R. When injected subcutaneously,intermediate-acting insulin generally reaches the bloodstream about 2 to4 hours after injection and is effective for about 12 to 18 hours. Typesof intermediate-acting insulin include: NPH (Humulin N, Novolin N). Wheninjected subcutaneously, long-acting insulin generally reaches thebloodstream several hours after injection and is effective over a24-hour period. Types of long-acting insulin include: Insulin detemir(Levemir) and insulin glargine (Lantus). In certain embodiments, theadministering comprises administering to the subject in need thereof theliver-selective glucokinase activator in combination with an insulin,such as a rapid-acting insulin, a short-acting insulin, anintermediate-acting insulin, a long-acting insulin, or a combination ofinsulins. In some embodiments, the combination of insulin administeredmay comprise a rapid-acting and a short-acting insulin. In otherembodiments, the combination of insulin administered may comprise anintermediate-acting insulin and a long-acting insulin. In otherembodiments, the combination of insulin administered may comprise anycombination of two, three, or four types of insulin. In some otherembodiments, the administering comprises administering to a subject inneed thereof a liver-selective glucokinase activator in combination withinsulin lispro, insulin aspart, insulin glulisine, isophane insulin,insulin zinc, insulin glargine, insulin detemir, or any combinationsthereof.

Subjects

The disclosed methods may be carried out on any suitable subjects,including humans, horses, cows, sheep, pigs, mice, rats, dogs, cats, andprimates such as chimpanzees, gorillas, and rhesus monkeys. In someembodiments, the subject is a human.

In the methods disclosed herein, the subject is a subject in need of theadministration of the treatment. In some embodiments, this includes asubject exhibiting one or more of the following symptoms: (i) a fastingblood-glucose concentration of greater than 100 mg/dL, or greater than110 mg/dL, or greater 100 or 110 mg/mL and less than 125 mg/dL; (ii) a2-hour postprandial plasma-glucose level greater than 140 mg/dL or a3-hour postprandial plasma-glucose level greater than 140 mg/dL; (iv)having an HbA1c value equal to or greater than 5.7%, 6.5%, 7.0%, 7.5% or8.0%; or (v) persistent presence of two or more islet antibodies.

The nature of the subject's need depends on the therapeutic goals. Insome embodiments of any of the foregoing embodiments, the subjectexhibits elevated levels of glycated hemoglobin in its blood, forexample, elevated levels of HbA1c in its blood. In some suchembodiments, administering the liver-selective GK activator incombination with insulin or an analog thereof is carried out to reducethe subject's glycated hemoglobin levels, such as the subject's HbA1clevels. In some embodiments, other measures of glycemic control areachieved (such as reduction of time in hypoglycemic range or reductionin number of hypoglycemic or severe hypoglycemic events) in combinationwith a reduction in HbA1c or without any reduction in HbA1c levels orwith a slight increase in HbA1c levels.

In some other embodiments, the subject exhibits one or more symptomsconsistent with type 1 diabetes. In some such embodiments, administeringthe liver-selective GK activator in combination with insulin or ananalog is carried out to treat type 1 diabetes (including treating oneor more of the symptoms associated therewith). In some otherembodiments, the subject has elevated body mass, or in some cases,obesity. In some such embodiments, administering the liver-selective GKactivator in combination with insulin or an analog thereof is carriedout to reduce body mass. In some other embodiments, the subject exhibitsone or more symptoms consistent with poor glycemic control, such as an ahigher percentage of time outside of target blood-glucose range (e.g.,in a hypoglycemic range or in a hyperglycemic range). In some suchembodiments, administering the liver-selective GK activator incombination with insulin or an analog thereof is carried out to increasethe percentage of time in target blood-glucose range, decrease thepercentage of time in hyperglycemic range, decrease the percentage oftime in hypoglycemic range, or reduce number of hypoglycemic or severehypoglycemic events over a period of time. Thus, in some suchembodiments, administering the liver-selective glucokinase activator incombination with insulin or an analog thereof is carried out to reducethe bolus insulin dose or doses, the bolus insulin dose at each meal,the basal insulin dose or doses, or total insulin dose over a period oftime. In some embodiments, the subject exhibits elevated mean dailyblood-glucose levels. Thus, in some such embodiments, administering theliver-selective glucokinase activator in combination with insulin or ananalog thereof is carried out to reduce mean daily blood-glucose levels.In some embodiments, the subject experiences an increased risk ofdiabetic ketoacidosis. Thus, in some embodiments, administering theliver-selective glucokinase activator in combination with insulin or ananalog thereof is carried out to reduce the incidence, duration, orlikelihood of ketoacidosis.

Doses of GK Activator

Any suitable dose and dosing schedule of the liver-selective GKactivator can be used. In some embodiments, the methods disclosed hereincomprise administering from 1 to 30 mg/kg daily of the liver-selectiveGK activator. These quantities may be administered in any suitableregimen throughout the day. In some embodiments, the administeringcomprises administering the liver-selective GK activator one or moretimes a day, such as one time a day, two times a day, three times a day,and the like. In some further such embodiments, the administeringcomprises administering the liver-selective GK activator two times aday. The administering may occur with or without food. In someembodiments wherein the administering comprises administering theliver-selective GK activator one or more times a day, at least one ofthe one or more times is with food. In some such embodiments, theadministering comprises administering the liver-selective GK activatortwo times a day with food. In some embodiments, the two or more dailydoses contain equal amounts of the liver-selective GK activator. Inother embodiments, the methods include administering from 1 to 30 mg/kgevery other day of the liver-selective GK activator, or every third day,or every fourth day, or every fifth day, every sixth day. A singleadministered dosage form may comprise between 1-75 mg, 75-100 mg, 75-150mg, 100-150 mg, 125-175 mg, 150-200 mg, 175-225 mg, 200-250 mg, 225-275mg, 250-300 mg, 275-325 mg, 300-350 mg, 325-375 mg, 350-400 mg, 375-425mg, 400-450 mg, 425-475 mg, 450-500 mg, 475-525 mg, 500-550 mg, 525-575mg, 550-600 mg, 575-625 mg, 600-650 mg, 625-675 mg, 675-725 mg, 700-750mg, 725-800 mg, or 775-825 mg of liver-selective GK activator. In otherembodiments, a liver-selective is administered in one or more doses to asubject in an amount that ranges from 100 mg/day to 2000 mg/day, or from200 mg/day to 1500 mg/day, or from 400 mg/day to 1200 mg/day, or from500 mg/day to 1200 mg/day, or from 800 mg/day to 1200 mg/day.

The duration of the methods disclosed herein may be carried out over anysuitable period of time, depending on treatment goals. Because type 1diabetes and its related disorders are chronic conditions, theadministering may, in some embodiments, be carried out indefinitely,such as for several years or more. In some embodiments, theadministering comprises administering the liver-selective GK activatorfor a period of time no less than one week, or no less than two weeks,or no less than three weeks, or no less than six weeks, or no less thannine weeks, or no less than twelve weeks.

Administration of the insulin or analog thereof can be carried out usingany suitable method. For example, in some embodiments, the insulin oranalog thereof is administered in conjunction with continuous glucosemonitoring, such that the insulin or analog thereof is administered asneeded depending on glucose levels.

Other Antidiabetic Agents

In some embodiments of any of the foregoing aspects and embodiments, theliver-selective GK activator and insulin or analog thereof can also beco-administered with one or more other antidiabetic agents. In thiscontext, the terms “coadministering” does not necessarily imply that theantidiabetic agents are administered on the same schedule as theliver-selective GK activator or insulin or analog thereof. After all, insome instances, these medications may be once-daily or once-weeklymedications. Thus, in this context, the term “coadministering” refers toadministering the drugs in such a way that the one or more otherantidiabetic agents have a non-zero concentration in the blood of thesubject at the time of administering the liver-selective GK activator.In some embodiments, the liver-selective GK activator and one or moreantidiabetic agents are formulated into the same dosage form, such as atablet or capsule for oral administration. In other embodiments, theyare formulated separately, and administered in a suitable means for therespective dosage forms.

Any suitable antidiabetic agents can be used. For example, in someembodiments, the one or more antidiabetic agents are selected from thegroup consisting of: biguanides (including metformin, phenformin, andbuformin), thiazolidinediones (including rosiglitazone, pioglitazone,and troglitazone), sulfonylureas (including tolbutamide, acetohexamide,tolazamide, chlorpropamide, glipizide, glibenclamide, glimepiride,gliclazide, glyclopyramide, and gliquidone), meglitinides (includingrepaglinide and nateglinide), alpha-glucosidase inhibitors (includingmiglitol, acarbose, and voglibose), glucagon-like peptide analogs andagonists (including exenatide, liraglutide, semaglutide, taspoglutide,lixisenatide, albuglutide, and dulaglutide), gastric inhibitory peptideanalogs, dipeptidyl peptidase-4 (DPP-4) inhibitors (includingvildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin,septagliptin, teneligliptin, and gemigliptin), amylin agonist analogs,sodium/glucose cotransporter inhibitors (such as dual SGLT1 and SGLT2inhibitors or selective SGLT2 inhibitors), and glucagon-like peptide(GLP) analogs and agonists. In some such embodiments, the one or moreantidiabetic agents is metformin. In another such embodiment, the one ormore antidiabetic agents is a sodium/glucose cotransporter inhibitorsuch as sotagliflozin, empagliflozin, dapagliflozin, canagliflozin, orertugliflozin.

In embodiments where metformin is coadministered in combination with theliver-selective GK activator, the coadministering comprises orallycoadministering from 1 to 30 mg/kg daily of metformin to the subject orcoadministering between 1 mg to 2,500 mg daily of metformin to thesubject. This coadministering can occur in any suitable dosages. In someembodiments, the coadministering comprises coadministering metformin oneor more times a day, such as one time a day, two times a day, threetimes a day, four times a day, and the like. In some such embodiments,the coadministering comprises coadministering metformin two times a day.In some further such embodiments, the coadministering comprisescoadministering metformin two times a day with food. In someembodiments, the two or more daily doses contain equal amounts ofmetformin. In some further embodiments of any of the foregoing aspectsand embodiments, coadministering metformin comprises administering to asubject in need thereof from 1 to 25 mg/kg daily of metformin. In someother such embodiments, coadministering metformin comprisescoadministering to a human subject in need thereof from 100 to 2000 mgdaily of metformin.

In some other such embodiments where an SGLT inhibitor is coadministeredwith the liver-selective GK activator, the coadministration comprisesorally administering a daily dose of an SGLT inhibitor at or below thedaily dose provided on the related product insert for the SGLTinhibitor.

Uses for Lowering Glycated Hemoglobin

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of lowering glycated hemoglobin levels in a subject. In somefurther such embodiments, lowering glycated hemoglobin levels compriseslowering HbA1c levels in a subject. For example, in some embodiments,lowering glycated hemoglobin levels comprises lowering HbA1c levels in asubject by an absolute amount of at least 0.1%, of at least 0.3%, or anabsolute amount of at least 0.5%, or an absolute amount of at least0.7%, or an absolute amount of at least 0.9%, or an absolute amount ofat least 1.0%, where HbA1c levels are measured as a percentage accordingto the National Glycohemoglobin Standardization Program (NGSP) protocol.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof for use inlowering elevated glycated hemoglobin levels in a subject according toany of the embodiments set forth above. In some other embodiments of anyof the foregoing aspects and embodiments, the disclosure provides usesof liver-selective GK activators in the manufacture of a medicament foruse in combination with insulin or analogs thereof for lowering elevatedlevels of glycated hemoglobin in a subject, wherein the medicament isprepared to be administered to a subject according to any of the methodsset forth above.

In other embodiments herein, achievement of measures of improvedglycemic control may be achieved without any reduction in HbA1c levelsor even with an increase in HbA1c levels.

Uses for Treating Diabetes

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of treating type 1 diabetes. In other embodiments of any ofthe foregoing aspects and embodiments, the methods are methods oftreating type 2 diabetes in a subject that is using insulin with orwithout another antidiabetic agent to regulate blood glucose levels.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof for treatingtype 1 diabetes according to any of the embodiments set forth above. Insome other embodiments of any of the foregoing aspects and embodiments,the disclosure provides uses of liver-selective GK activators in themanufacture of a medicament for use in combination with insulin oranalogs thereof for treating type 1 diabetes, wherein the medicament isprepared to be administered to a subject according to any of the methodsset forth above.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof for treatingtype 2 diabetes in a subject that is also using insulin to regulateblood glucose levels with or without another antidiabetic agentaccording to any of the embodiments set forth above. In some otherembodiments of any of the foregoing aspects and embodiments, thedisclosure provides uses of liver-selective GK activators in themanufacture of a medicament for use in combination with insulin oranalogs thereof for treating type 2 diabetes in a subject that is alsousing insulin to regulate blood glucose levels with or without anotherantidiabetic agent, wherein the medicament is prepared to beadministered to a subject according to any of the methods set forthabove.

Uses for Reducing Body Mass

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of reducing body mass. In some further such embodiments, themethods comprise reducing body-mass index (BMI) of a subject havingelevated BMI levels by an absolute amount of at least 0.5, or at least1.0, or at least 1.5, or at least 2.0. In other embodiments, thesubject's body weight may be reduced by at least 0.1, or 0.2, or 0.3, or0.4, or 0.5, or 0.6, or, 0.7, or 0.8, or 0.9, or 1.0, or 1.5, or 2.0 kg.In another embodiment, the subject's BMI or body weight is reduced overa period of 1, 2, 3, 4, 5, 6, 7, or 8 week(s), or 3, 4, 5 or 6 months.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof in reducingbody mass according to any of the embodiments set forth above. In someother embodiments of any of the foregoing aspects and embodiments, thedisclosure provides uses of liver-selective GK activators in themanufacture of a medicament for use in combination with insulin oranalogs thereof for reducing body mass, wherein the medicament isprepared to be administered to a subject according to any of the methodsset forth above.

Uses for Improving Glycemic Control

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of improving glycemic control.

In some embodiments, the methods are methods of increasing thepercentage of time in target blood-glucose range, i.e., for humans,within a range of from 70 mg/dL to 180 mg/dL per unit time. In some suchembodiments, the methods comprise increasing the percentage time intarget blood-glucose range by an absolute percentage of at least 1%, atleast 2%, at least 3%, at least 4%, at least 5%, at least 6%, or atleast 8%, or at least 10%, or at least 12%, or at least 14%, based onthe absolute difference of percentage of time in target blood-glucoserange for a period of time relative to baseline (such as administeringonly insulin or an analog thereof).

In other embodiments, the methods are methods of increasing percentageof time between meals (such as 2 hours after previous meal andimmediately before next meal) in blood glucose range of 80-130 mg/dL.(Pre-prandial range). In other embodiments, the methods are methods ofincreasing percentage of time after beginning of meal and ending 2 hoursafter meal in blood glucose level of less than or equal to 180 mg/dL.The percentage of increase of time in these methods may be an absolutepercentage of at least 1%, at least 2%, at least 3%, at least 4%, atleast 5%, at least 6%, or at least 8%, or at least 10%, or at least 12%,or at least 14%, based on the difference of percentage of time in targetblood-glucose range relative to baseline (such as administering onlyinsulin or an analog thereof).

In some embodiments, the methods are methods of decreasing thepercentage of time in hypoglycemic range or severe hypoglycemic range.In some such embodiments, the methods comprise decreasing the percentagetime in hypoglycemic range or severe hypoglycemic range by an absolutepercentage of at least 1%, at least 2%, at least 3%, at least 4%, atleast 5%, at least 6%, or at least 8%, or at least 10%, or at least 12%,or at least 14%, based on the absolute difference of percentage of timein target blood-glucose range for a period of time relative to baseline(such as administering only insulin or an analog thereof).

In some embodiments, the methods are methods of decreasing thepercentage of time in hyperglycemic range or severe hyperglycemic range.In some such embodiments, the methods comprise decreasing the percentagetime in hyperglycemic range or severe hyperglycemic range by an absolutepercentage of at least 1%, at least 2%, at least 3%, at least 4%, atleast 5%, at least 6%, or at least 8%, or at least 10%, or at least 12%,or at least 14%, based on the absolute difference of percentage of timein target blood-glucose range relative to baselines (such asadministering only insulin or an analog thereof).

In some embodiments, the methods are methods of reducing the number ofhypoglycemic events or severe hypoglycemic events over a period of time.In some such embodiments where the subject is using CGM, the methodscomprise reducing the number of hypoglycemic events or severehypoglycemic events over a period of time by an absolute amount of atleast 1 event or 2 events. In other such embodiments where the subjectis using SMBG, the methods comprise reducing the number of hypoglycemicevents or severe hypoglycemic events over a period of time by anabsolute amount of at least 1 event, 2 events, 10 events, 20 events, 30events, 50 events, 70 events. In some embodiments, the period of timemay be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.

In other embodiments, the methods comprise reducing the number ofhyperglycemic events or severe hyperglycemic events over a period oftime. In some such embodiments where the subject is using CGM, themethods comprise reducing the number of hyperglycemic events or severehyperglycemic events over a period of time by an absolute amount of atleast 1 event or 2 events. In other such embodiments where the subjectis using SMBG, the methods comprise reducing the number of hyperglycemicevents or severe hyperglycemic events over a period of time by anabsolute amount of at least 1 event, 2 events, 10 events, 20 events, 30events, 50 events, 70 events. In some embodiments, the period of time is1 day, or 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof in increasingthe percentage of time in target blood-glucose range, decreasing thepercentage of time in hypoglycemic range, decreasing the percentage oftime in hyperglycemic range, decreasing the time in severe hypoglycemicrange, reducing the number of hyperglycemic events, or reducing thenumber of severe hypoglycemic events, according to any of theembodiments set forth above. In some other embodiments of any of theforegoing aspects and embodiments, the disclosure provides uses ofliver-selective GK activators in the manufacture of a medicament for usein combination with insulin or analogs thereof in increasing thepercentage of time in target blood-glucose range, decreasing thepercentage of time in hypoglycemic range, decreasing the percentage oftime in hyperglycemic range, decreasing the time in severe hypoglycemicrange, reducing the number of hyperglycemic events, or reducing thenumber of severe hypoglycemic events wherein the medicament is preparedto be administered to a subject according to any of the methods setforth above.

Uses for Lowering Insulin Dose

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of reducing insulin (or analog thereof) doses for a subjectfor example on a per dose basis, per day basis, or per week basis, orother period. In some further such embodiments, the methods comprisereducing insulin (or analog thereof) dose by at least 1%, at least 2%,at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, atleast 15%, at least 20%, or at least 25%, or by an absolute amount of atleast 1 unit, 2 units, 3 units, 4 units, 5 units, 6 units, 7 units, 8units, 9 units, or 10 units based on the baseline insulin (or analogthereof) dose (such as treatment only with insulin or an analogthereof).

Uses for Reducing Total Daily Bolus Insulin Dose

In some embodiments, the methods are methods of reducing the total dailybolus insulin dose. In some such embodiments, the methods comprisereducing total daily bolus insulin (or analog thereof) dose by at least1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, atleast 10%, at least 15%, at least 20%, or at least 25%, or by anabsolute amount of at least 1 unit, 2 units, 3 units, 4 units, 5 units,6 units, 7 units, 8 units, 9 units, or 10 units based on the baselinetotal daily bolus insulin (or analog thereof) dose (such as treatmentonly with insulin or an analog thereof).

Uses for Reducing Total Daily Basal Insulin Dose

In some embodiments, the methods are methods of reducing the total dailybasal insulin dose. In some such embodiments, the methods comprisereducing total daily basal insulin (or analog thereof) dose by at least1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 7%, atleast 10%, at least 15%, at least 20%, or at least 25%, or by anabsolute amount of at least 1 unit, 2 units, 3 units, 4 units, 5 units,6 units, 7 units, 8 units, 9 units, or 10 units based on the baselinetotal daily basal insulin (or analog thereof) dose (such as treatmentonly with insulin or an analog thereof).

Uses for Reducing Total Daily Insulin Dose

In some embodiments, the methods are methods of reducing the total dailyinsulin dose. In some such embodiments, the methods comprise reducingtotal daily insulin (or analog thereof) dose by at least 1%, at least2%, at least 3%, at least 4%, at least 5%, at least 7%, at least 10%, atleast 15%, at least 20%, or at least 25%, or by an absolute amount of atleast 1 unit, 2 units, 3 units, 4 units, 5 units, 6 units, 7 units, 8units, 9 units, or 10 units based on the baseline total daily insulin(or analog thereof) dose (such as treatment only with insulin or ananalog thereof).

Uses for Reducing the Number or Doses of Insulin Injections

In some embodiments, the methods are methods of reducing the number ofinsulin injections over a period of time, where the period of time maybe 1 days, 1 week, or 1 month. In some embodiment, the total number ofinsulin injections may be reduced by 1, 2, 3, or more. In otherembodiments, the methods are methods of reducing the number of dailybasal insulin injections, where the number of injections may be reducedby 1, 2, 3, or more. In other embodiments, the methods are methods ofreducing the number of daily bolus insulin injections, where the numberof injections may be reduced by 1, 2, 3, or more. In another embodiment,the number of insulin injections per day are no more than 1 or 2 or 3.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof in loweringinsulin doses or injection according to any of the embodiments set forthabove. In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in the manufacture of a medicament for use in combinationwith insulin or analogs thereof for lowering insulin doses orinjections, wherein the medicament is prepared to be administered to asubject according to any of the methods set forth above.

Uses for Lowering Mean Daily Blood-Glucose

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of reducing mean daily blood-glucose levels. In some furthersuch embodiments, the methods comprise reducing mean daily blood-glucoselevels by at least 5 mg/dL, or at least 7 mg/dL, or at least 10 mg/dL,or at least 15 mg/dL, or at least 20 mg/dL, or at least 25 mg/dL, or atleast 30 mg/dL, or at least 35 mg/dL relative to baseline treatment(such as using only insulin or an analog thereof).

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof in loweringmean daily blood-glucose levels according to any of the embodiments setforth above. In some other embodiments of any of the foregoing aspectsand embodiments, the disclosure provides uses of liver-selective GKactivators in the manufacture of a medicament for use in combinationwith insulin or analogs thereof for lowering mean daily blood-glucoselevels, wherein the medicament is prepared to be administered to asubject according to any of the methods set forth above.

Uses for Lowering Glucagon Levels

Glucagon is a polypeptide hormone that is produced by the alpha cells ofthe pancreas. It is a hyperglycemic agent that mobilizes glucose byactivating hepatic glycogenolysis (the breakdown of glycogen especiallyinto glucose). However, excess levels of glucagon may lead to temporarychanges in blood pressure, increased heart rate, nausea, vomiting,and/or hyperglycemia and certain antidiabetic drugs, such as SGLT2inhibitors, may trigger excessive glucagon secretion.

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of reducing plasma glucagon levels and/or not increasingplasma glucagon levels. In some further such embodiments, the methodscomprise reducing glucagon levels by at least 5 pg/mL, or at least 10pg/mL, or at least 25 pg/mL, or at least 30 pg/mL, or at least 35 pg/mL,or at least 50 pg/mL, or at least 75 pg/mL relative to baselinetreatment (such as using only insulin or an analog thereof) or reducingglucagon levels below 200 pg/mL, or below 150 pg/mL, or below 100 pg/mL.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof in loweringplasma glucagon levels according to any of the embodiments set forthabove. In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in the manufacture of a medicament for use in combinationwith insulin or analogs thereof for lowering plasma glucagon levels,wherein the medicament is prepared to be administered to a subjectaccording to any of the methods set forth above.

Uses for Reducing Incidence, Duration, or Likelihood of DiabeticKetoacidosis

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of reducing the incidence, duration, or likelihood ofdiabetic ketoacidosis. In an embodiment, diabetic ketoacidosis isdefined as a subject having elevated level of one or more metabolicketones such as serum or urine ketones (greater than upper limit ofnormal range), and having a blood pH of 7.3 or less and a serumbicarbonate level of 18 mmol/L or less. In another embodiment, diabeticketoacidosis is defined as a subject having elevated plasma, serum orurine ketones (greater than upper limit of normal range), or having ablood pH of less than 7.3 or a serum bicarbonate level of 18 mmol/L orless, or 15 mmol/L or less or the equivalent measure in mEq/L, or bloodglucose level of greater than 250 mg/dL, or a combination of any of theforegoing measures. In an embodiment, the metabolic ketone is selectedfrom the group consisting of acetoacetate (AcAc), beta-hydroxybutyrate(BHB), and acetone. In a further embodiment, the level of AcAc ismeasured in the subject's serum. In another embodiment, the level of BHBis measured in the subject's urine. In another embodiment, the level ofBHB is measured in the subject's blood. In a further embodiment, thelevel of one or more of metabolic ketones is between 0.3 and 0.5 mM, orgreater than 0.5 mM, or between 0.5 and 1.0 mM, or between 1.0 and 3.0mM, or greater than 3.0 mM, or 4.0 mM, or 5.0 mM, 10 mM, or 15 mM, or 20mM. In some further such embodiments, the methods comprise reducing theincidence of diabetic ketoacidosis by at least 5%, or at least 10%, orat least 15%, relative to baseline treatment (such as using only insulinor an analog thereof), over a relevant period of time, such as one week,one month, two months, three months, etc.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof in reducingthe incidence, duration, or likelihood of diabetic ketoacidosisaccording to any of the embodiments set forth above. In some otherembodiments of any of the foregoing aspects and embodiments, thedisclosure provides uses of liver-selective GK activators in themanufacture of a medicament for use in combination with insulin oranalogs thereof for reducing the incidence, duration, or likelihood ofdiabetic ketoacidosis, wherein the medicament is prepared to beadministered to a subject according to any of the methods set forthabove.

Uses for Reducing Incidence, Duration, or Likelihood of Diabetic Ketosis

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of reducing the incidence, duration, or likelihood ofdiabetic ketosis. In an embodiment, diabetic ketosis is defined as asubject having elevated metabolic ketones such as serum or urine ketones(greater than upper limit of normal range), and while having blood sugarand or blood pH in normal range. For example, diabetic ketosis may occurwhen a subject's blood pH is equal to or above pH of 7.3 and/or has aserum bicarbonate level of greater than 15 mmol/L, 18 mmol/L, or 20mmol/L. In further embodiments, subject's blood glucose level is lessthan 250 mg/dL or less than 200 mg/dL, or less than 180 mg/dL. In anembodiment, the metabolic ketone indicating an incidence of diabeticketosis is selected from the group consisting of acetoacetate (AcAc),beta-hydroxybutyrate (BHB), and acetone. In a further embodiment, thelevel of AcAc is measured in the subject's blood or urine. In anotherembodiment, the level of BHB is measured in a sample taken from thesubject's blood or urine. In another embodiment, the level of acetone ismeasured in a sample of the subject's breath. In a further embodiment,the level of one or more of metabolic ketones indicating diabeticketosis is between 0.3 and 0.5 mM, or greater than 0.5 mM, or between0.5 and 1.0 mM, or between 1.0 and 3.0 mM, or between 3.0 mM and 6.0 mM,or between 6.0 mM and 10 mM, or greater than 5 mM or 10 mM or 15 mM or20 mM or 25 mM. In some further such embodiments, the methods comprisereducing the incidence of diabetic ketosis by at least 5%, or at least10%, or at least 15%, relative to baseline treatment (such as using onlyinsulin or an analog thereof), over a relevant period of time, such asone week, one month, two months, three months, etc. In some otherembodiments of any of the foregoing aspects and embodiments, thedisclosure provides uses of liver-selective GK activators in combinationwith insulin or analogs thereof in reducing the incidence, duration, orlikelihood of diabetic ketosis according to any of the embodiments setforth above. In some other embodiments of any of the foregoing aspectsand embodiments, the disclosure provides uses of liver-selective GKactivators in the manufacture of a medicament for use in combinationwith insulin or analogs thereof for reducing the incidence, duration, orlikelihood of diabetic ketoacidosis, wherein the medicament is preparedto be administered to a subject according to any of the methods setforth above.

Uses for Reducing Metabolic Ketones

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of reducing the level of metabolic ketones in a subject. Inan embodiment, the metabolic ketones reduced are selected from the groupconsisting of acetoacetate (AcAc), beta-hydroxybutyrate (BHB), andacetone. In a further embodiment, the level of AcAc is reduced. Inanother embodiment, the level of BHB is reduced. In another embodiment,the level of one or more metabolic ketone(s) is reduced by at least 0.1mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, or 0.9 mM,or reduced by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%, 35%, 40%,45%, or 50% relative to a baseline measurement, such as beforetreatment. In another embodiment, the level of BHB is reduced by atleast 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, or0.9 mM, or reduced by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%,35%, 40%, 45%, or 50% relative to a baseline measurement, such as beforetreatment. In another embodiment, the level of AcAc is reduced by atleast 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, or0.9 mM, or reduced by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%,35%, 40%, 45%, or 50% relative to a baseline measurement, such as beforetreatment. In another embodiment, the level of acetone is reduced by atleast 0.1 mM, 0.2 mM, 0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, or0.9 mM, or reduced by at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 30%,35%, 40%, 45%, or 50% relative to a baseline measurement, such as beforetreatment. In some further such embodiments, the methods comprisereducing the level of one or more metabolic ketones relative to baselinetreatment (such as using only insulin or an analog thereof), over arelevant period of time, such as one week, one month, two months, threemonths, etc.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof in reducingthe level of metabolic ketones according to any of the embodiments setforth above. In some other embodiments of any of the foregoing aspectsand embodiments, the disclosure provides uses of liver-selective GKactivators in the manufacture of a medicament for use in combinationwith insulin or analogs thereof for reducing the level of metabolicketones, wherein the medicament is prepared to be administered to asubject according to any of the methods set forth above.

Uses for Reducing Incidence, Duration, or Likelihood of Diabetic LacticAcidosis

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of reducing the incidence, duration, or likelihood ofdiabetic lactic acidosis. In an embodiment, diabetic lactic acidosis isdefined as a subject having an elevated level of lactic acid such asabove 1.0 mM, 1.5 mM, 2.0 mM, 2.5 mM, 3.0 mM, 3.5 mM, 4.0 mM, 4.5 mM,5.0 mM, 10 mM, or 15 mM. In another embodiment, diabetic lactic acidosisis defined as a subject having elevated arterial blood lactateconcentration (such as above 14.4 mg/dL or 1.6 mM) or venous bloodlactate concentration (such as above 19.8 mg/dL or 2.2 mM), or anequivalent concentration of lactate concentration in capillary blood. Insome further such embodiments, the methods comprise reducing theincidence of diabetic lactic acidosis by at least 5%, or at least 10%,or at least 15%, relative to baseline treatment (such as using onlyinsulin or an analog thereof), over a relevant period of time, such asone week, one month, two months, three months, etc.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof in reducingthe incidence, duration, or likelihood of diabetic lactic acidosisaccording to any of the embodiments set forth above. In some otherembodiments of any of the foregoing aspects and embodiments, thedisclosure provides uses of liver-selective GK activators in themanufacture of a medicament for use in combination with insulin oranalogs thereof for reducing the incidence, duration, or likelihood ofdiabetic lactic acidosis, wherein the medicament is prepared to beadministered to a subject according to any of the methods set forthabove.

Uses for Reducing Lactate

The foregoing methods are set forth as general methods. In someembodiments of any of the foregoing aspects and embodiments, the methodsare methods of reducing the level of lactate in a subject. In anembodiment, the level of lactate is reduced by at least 0.1 mM, 0.2 mM,0.3 mM, 0.4 mM, 0.5 mM, 0.6 mM, 0.7 mM, 0.8 mM, 0.9 mM, 1.0 mM, 1.5 mM,2.0 mM, or reduced by at least 1 mg/dL, or 2 mg/dL, or 3 mg/dL, or 4mg/dL or 5 mg/dL or 10 mg/dL, or reduced to below 3.0 mM, or reduced tobelow 2.5 mM, or reduced to below 2.0 mM, or reduced to below 1.5 mM, orreduced to below 1.0 mM, or reduced by at least 1%, 2%, 3%, 4%, 5%, 10%,15%, 20%, 30%, 35%, 40%, 45%, or 50% relative to a baseline measurement,such as before treatment. In another embodiment, the level of lactate ismeasured in the arterial blood. In another embodiment, the level oflactate is measured in venous blood. In some further such embodiments,the methods comprise reducing the level of lactate relative to baselinetreatment (such as using only insulin or an analog thereof), over arelevant period of time, such as one week, one month, two months, threemonths, etc.

In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in combination with insulin or analogs thereof in reducingthe level of lactate according to any of the embodiments set forthabove. In some other embodiments of any of the foregoing aspects andembodiments, the disclosure provides uses of liver-selective GKactivators in the manufacture of a medicament for use in combinationwith insulin or analogs thereof for reducing the level of lactate,wherein the medicament is prepared to be administered to a subjectaccording to any of the methods set forth above.

Assays

The methods of treatment disclosed herein can include a step ofmeasuring one or more biomarkers before, during and/or after certainperiods of treatment. In an embodiment, the method may further compriseobtaining or having obtained a biological sample or samples over aperiod of time from the subject and performing or having performed abodily fluid test on the biological samples. The bodily fluid tests maybe used to determine the percentage of time in a target blood-glucoserange, the level of glycated hemoglobin, the percentage of time inhypoglycemic range, the percentage of time in hyperglycemic range, theincidence of or number incidences of diabetic ketoacidosis, theincidence of or number incidences of diabetic ketosis, the number ofhypoglycemic or severe hypoglycemic events over a period of time, thenumber of hyperglycemic or severe hypoglycemic events over a period oftime.

The biological sample or bodily fluid to be tested may includes fluidsproduced by the body, such as saliva, or fractions thereof, mucoussecretions, tears, sweat, bile, semen, urine, vaginal secretions,exhalations, anal secretions, blood, plasma, serum and mixtures ofthereof. In an embodiment, the biological sample or bodily fluid may besaliva, a mucous secretion, tears, sweat, urine, exhalate, blood, orserum.

The biomarkers that may be measured in the biological sample or bodilyfluid include glucose, metabolic ketone(s), glucagon, glycosylatedhemoglobin, lactate, and pH. In some embodiments, the method maycomprise measuring a subject's blood glucose level, blood serum pHlevel, or serum bicarbonate level, one or more metabolic ketone(s) in asubject's blood, breath, or urine, measuring the level of glucagonhormone in a subject's blood, the level of lactate in a subjects blood,and/or measuring the level of glycated hemoglobin in the subject'sblood, for example, levels of HbA1c in a subject's blood.

Biomarkers may be measured by any method known in the art. For example,glucose may be measured by using a continuous glucose monitoring deviceor glucose test strips. Blood pH may be measured by pH test strips, acalibrated pH meter. Glucagon may be measured by a radioimmunoassay oran ELISA assay. Urine ketone concentrations may be measured usingover-the-counter reagent strips which determine the presence of AcAcupon reaction with nitroprusside salt. Blood ketone concentrations maybe measured using an electrochemical capillary blood monitor device withthe corresponding individually foil-wrapped test strips for BHB.Glycosylated hemoglobin may be measured using high-performance liquidchromatography, an immunoassay, an enzymatic assay, capillaryelectrophoresis, or boronate affinity chromatography. Lactate may bemeasured using a blood gas analyzer. Lactate may be measured by aportable/point of care analyzer such as those using enzymatic (lacticoxidase) amperometric detection methods, or may be measured by a deviceusing an electrical amperometric metabolite sensor or ion selectiveelectrode.

In another embodiment, the method may comprise the step of selecting asubject for treatment. In some embodiments, the subject is selected fortreatment by determining whether a subject is at risk of developingdiabetic ketoacidosis by measuring the level of a subject's bloodglucose, blood pH, serum pH, serum bicarbonate, and/or one or moremetabolic ketone(s) in a subject's. A subject may be at risk ofdeveloping diabetic ketoacidosis if the subject is determined to sufferfrom diabetic ketosis for example by having elevated levels of one ormore metabolic ketones while not having abnormal blood sugar leveland/or blood pH below 7.3. In embodiment, if a subject is determined tobe at risk for developing diabetic ketoacidosis, the method furthercomprises administering to the subject a liver-selective glucokinaseactivator in combination with insulin or an analog thereof.

In other embodiments, the subject may be selected for treatment when thesubject is in need of therapeutic lowering of metabolic ketone levels,therapeutic lowering of glucagon levels, therapeutic lowering of lactatelevels, therapeutic lowering of blood sugar levels, therapeutic loweringof HbA1c levels, or therapeutic elevating of plasma pH levels. Thus, themethod may first include the step of identifying whether a subject is inneed of therapeutic lowering of metabolic ketone levels, therapeuticlowering of glucagon levels, therapeutic lowering of lactate levels,therapeutic lowering of blood sugar levels, therapeutic lowering ofHbA1c levels, or therapeutic elevating of plasma pH levels. In anembodiment, the subject is identified for treatment after obtaining orhaving obtained a biological sample from the subject and performing orhaving performed a bodily fluid test on the biological sample todetermine if the level of one or more biomarkers is associated with theneed for a therapeutic modulation of its level.

In other embodiments, the subject may be selected for treatment when acombination of clinical symptoms, clinical events, and/or biomarkerlevels are identified. For example, a subject may be selected fortreatment if the subject has had more than 1, 2, 3, 4, or 5hyperglycemic events, severe hyperglycemic events, hypoglycemic events,or severe hypoglycemic events over a certain period. A subject may alsobe selected for treatment if the subject has elevated levels of one ormore metabolic ketones, suffers from euglycemic ketoacidosis, has ablood pH at or below 7.3, has an HbA1c above 6.0, 6.5, 7.0, 7.5, 8.0,8.5, or 9.0%, has elevated levels of lactate such as above 1.0 mM, or2.0 mM, or 3.0 mM, or 4.0 mM and/or has a level of glucagon above 100pg/mL, 130 pg/mL, 150 pg/mL, or 200 pg/mL or a combination of any of theforegoing. In any of the preceding methods, the method may furthercomprise obtaining or having obtained biological samples over a periodof time from the subject and performing or having performed a bodilyfluid test on the biological samples to determine whether the level ofone or more biochemical markers are increasing or decreasing, and if thelevel of one or more biochemical markers are not trending in the desireddirection then administering a greater dose of the liver-selectiveglucokinase activator.

Pharmaceutical Compositions Dosage Forms

The liver-selective GK activators can be formulated into any suitablepharmaceutical composition. As used herein, the term “pharmaceuticalcomposition” refers to a composition (e.g., a granulated powder or aliquid) that contains a pharmaceutically active ingredient (e.g., aliver-selective GK activators) and a pharmaceutically acceptablecarrier. As used herein, the term “pharmaceutically acceptable” refersto a substance that is not generally biologically undesirable at theadministered quantities.

A single administered dosage form of a liver-selective GK activator maycomprise between 1-75 mg, 75-100 mg, 75-150 mg, 100-150 mg, 125-175 mg,150-200 mg, 175-225 mg, 200-250 mg, 225-275 mg, 250-300 mg, 275-325 mg,300-350 mg, 325-375 mg, 350-400 mg, 375-425 mg, 400-450 mg, 425-475 mg,450-500 mg, 475-525 mg, 500-550 mg, 525-575 mg, 550-600 mg, 575-625 mg,600-650 mg, 625-675 mg, 675-725 mg, 700-750 mg, 725-800 mg, or 775-825mg of the liver-selective GK activator.

In some embodiments, the liver-selective GK activators is included inseparate pharmaceutical composition from any coadministered antidiabeticagents (such as metformin or an SGLT2 inhibitor), each of which alsoincludes a pharmaceutically acceptable carrier. In other embodiments,the liver-selective GK activators is included in the same pharmaceuticalcomposition with one or more coadministered antidiabetic agents (such asmetformin or an SGLT2 inhibitor), which also includes a pharmaceuticallyacceptable carrier.

The pharmaceutical compositions, described herein, can be packaged in aform for oral administration as discrete units (i.e., dosage forms),such as capsules, tablets, sachets, or the like. Preparation of thesolid compositions in forms intended for oral administration is withinthe ability of one skilled in the art, including the selection ofpharmaceutically acceptable additional ingredients from the groupslisted above in order to provide pharmaceutically elegant and palatablepreparations. Such pharmaceutical compositions may be prepared bymethods known in the pharmaceutical formulation art, for example, seeRemington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company,Easton, Pa., 1990).

EXAMPLES Example 1—Study Design

An open-label, weekly dose escalation study with up to 3 doseescalations was conducted. Five adult patients with type 1 diabetes(T1DM) who were using a continuous glucose monitoring (CGM) device andinsulin delivered by continuous subcutaneous insulin infusion (CSII)were dosed with a once daily with a dose of 400, 800 or 1200 mg of{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid (UT-1) for seven days at each dose level.

The initial 7 days (days −7 to −1) of the study were used to obtainbaseline laboratory samples and to record baseline insulin doses andblood glucose levels during a patient's usual insulin, dietary, andactivity regimen. The once daily treatment dose of UT-1 was administeredmorning meal. Safety labs were collected on days −7, 1, 8, 15, 21 and28. Insulin pump data and CGM data for each dosing period was collectedon days 1, 8, 15, 21, and 28. Insulin was adjusted by a patient asrequired to maintain glycemic control. Data from day 3 to day 6 of eachdosing period or baseline period was used in the analysis of the data.

Results

No detrimental effect on liver function or plasma lipids was seen duringthe study. As shown in the data below and in the related figures, trendstoward improved glycemic control while reducing insulin dose were alsoseen. Further trends toward improved glycemic control were seen in anincrease in the ratio of mean carbohydrate intake per day to mean bolusinsulin dose per day ratio from baseline to 400 mg dose, and from 400 mgdose to 800 mg dose. Pharmacokinetic data indicated that the 1200 mggroup concentrations of UT-1 were lower in 3 out of 5 subjects whencompared to the 800 mg group.

In FIG. 1, the median value of the percentage of time blood glucoselevels were in the range of 70-180 mg/dL increased from baseline (52.0%)to the 400 mg dose (67.9%), and from the 400 mg dose (67.9%) to the 800mg dose (75.7%). The data used to prepare FIG. 1 is provided in Table 1below.

TABLE 1 Percentage of time (using CGM) blood glucose level is in rangeof 70-180 mg/dL for each at baseline and at each dose. Dose of UT-1Baseline 400 mg 800 mg 1200 mg Subject (%) (%) (%) (%) 1 49.7 67.9 82.769.6 2 80.0 56.8 75.7 59.3 3 52.0 69.3 44.3 52.9 4 47.2 56.3 65.4 48.8 560.5 69.6 85.9 80.9Each data point in Table 1 represents the median of four days (days 3-6)at each dose for each subject.The data used to prepare FIG. 2 is provided in Table 2.

TABLE 2 Percentage of time (using CGM) blood glucose level is between 54and 70 mg/dL for each subject at baseline and at each dose. Dose of UT-1Baseline 400 mg 800 mg 1200 mg Subject (%) (%) (%) (%) 1 1.39 0.54 0.691.28 2 1.89 4.97 0 5.84 3 4.9 4.2 3.27 0.17 4 0.2 0.86 0 0.17 5 6.035.54 0.17 0.86Each data point in Table 2 represents the median of four days (days 3-6)at each dose for each subject.The data used to prepare FIG. 3 is provided in Table 3.

TABLE 3 Percentage of time (using CGM) blood glucose level is below 54mg/dL for each subject at baseline and at each dose. Dose of UT-1Baseline 400 mg 800 mg 1200 mg Subject (%) (%) (%) (%) 1 0 0 0 0 2 01.88 0 3.84 3 0.62 0 1.38 0 4 0 0 0 0 5 1.21 2.42 0 0Each data point in Table 3 represents the median of four days (days 3-6)at each dose for each subject.

In FIG. 4, the median value of the percentage of time blood glucoselevels were greater than 180 mg/dL (hyperglycemia) decreased frombaseline (37%) to the 400 mg dose (30.92%), and from the 400 mg dose(30.92%) to the 800 mg dose (20.46%). The data used to prepare FIG. 4 isprovided in Table 4.

TABLE 4 Percentage of time (using CGM) blood glucose level is above 180mg/dL for each subject at baseline and at each dose. Dose of UT-1Baseline 400 mg 800 mg 1200 mg Subject (%) (%) (%) (%) 1 48.63 30.9216.82 24.62 2 11.69 36.99 20.46 30.09 3 37 20.91 50.66 42.24 4 50.8642.54 34.56 50.68 5 32.24 22.49 14.07 18.79Each data point in Table 4 represents the median of four days (days 3-6)at each dose for each subject.

In FIG. 5, the mean value of bolus insulin dose per day (mean U/day)decreased from baseline (27.1 mean U/day) to 400 mg (25 mean U/day), andfrom 400 mg to 800 mg (20 mean U/day).

The data used to prepare FIG. 5 is provided in Table 5.

TABLE 5 Mean units of bolus insulin units administered per day for eachsubject at baseline and at each dose. Dose of UT-1 Baseline 400 mg 800mg 1200 mg (mean (mean (mean (mean Subject U/day) U/day) U/day) U/day) 132.9 25.5 22 28 2 26.7 23.3 15.8 25.2 3 27.1 22.6 17.6 16.2 4 27.2 29.923.4 23.8 5 21.3 Not measured 22.5 20.9Each data point in Table 5 represents the mean of four days (days 3-6)at each dose for each subject.The data used to prepare FIG. 6 is provided in Table 6.

TABLE 6 Mean units of basal insulin units administered per day for eachsubject at baseline and at each dose. Dose of UT-1 Baseline 400 mg 800mg 1200 mg (mean (mean (mean (mean Subject U/day) U/day) U/day) U/day) 128.8 29.3 29.8 30.5 2 21.0 22.6 22.2 19.1 3 23.8 23.9 22.6 22.9 4 14.615.5 15.3 13.9 5 23.9 Not measured 19.6 21.8Each data point in Table 6 represents the mean of four days (days 3-6)at each dose for each subject.

Example 2—Study Design

A multi-center double-blind placebo-controlled study with a 2-weeksingle-blind placebo run-in period to evaluate UT-1 as a potentialadjunctive treatment to insulin therapy for T1DM was conducted. Thestudy examined the response in 20 adult patients with T1DM who wereusing a continuous glucose monitoring (CGM) device and insulin deliveredby continuous subcutaneous insulin infusion (CSII) dosed once daily witheither placebo or 800 mg UT-1 for up to 12 weeks. The once dailytreatment was administered with the morning meal. Safety and assessmentslabs were collected prior to the placebo-run in period, at Day 1 priorto dosing with blinded study medication, at weeks 2, 4, 6, 8, 12 and atapproximately week 13. Insulin pump data and CGM data was collected fromthe single-blind placebo run-in period to the end of dosing. A qualityof life and treatment satisfaction questionnaires were also used.Insulin was adjusted by patients as required to maintain glycemiccontrol.

Results

The baseline mean HbA1c for the groups treated with UT-1 and placebo was7.3% and 7.4%, respectively. Patients treated with UT-1 (n=8) showed astatistically significant mean reduction in HbA1c of 0.6% at 12 weeks(ending at HbA1c of between 6.7-6.8% at 12 weeks), while the grouptreated with placebo (n=11) showed a mean increase in HbA1c of 0.1%(ending at HbA1c of 7.5% at 12 weeks), resulting in a mean difference of0.7% in the UT-1 group relative to the placebo group (p=0.03). At thesame time, trends toward decreased insulin usage were observed in thegroup treated with UT-1.

Patients in this study received insulin adjustments to optimize glucoselevels. As a result, the primary analysis included a responder analysisin which a ‘treatment responder’ was defined as a patient who had adecrease in HbA1c at Week 12, no abnormal lactate (greater than 20mg/dL) or abnormal metabolic ketones (greater than 4.17 mg/dL of BHB)detected in blood or urine during the study, and no increased time inLevel 2 hypoglycemia (blood glucose <54 mg/dl). Of all study patients,there was a greater proportion of responders in the group treated withUT-1 (75%) than in the placebo group (9%) (p=0.006). Consistent with thetreatment responder results, abnormal levels of metabolic ketones wereobserved in plasma or urine in 63% of patients on placebo vs. 13% ofpatients treated with UT-1.

UT-1 was well tolerated with similar incidences of treatment-emergentadverse events overall and by system organ class. The study had noserious adverse event reported. The study also had no report of diabeticketoacidosis or severe hypoglycemia.

What is claimed is:
 1. A method of lowering glycated hemoglobin levelsin a human subject having type 1 diabetes, the method comprisingadministering to the human subject 400 mg/day to 1200 mg/day of{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof in combination withinsulin or an insulin analog, wherein the{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof is orallyadministered one time a day, and wherein the incidence of hypoglycemicevents in the human subject is reduced.
 2. The method of claim 1,wherein the glycated hemoglobin is HbA1c, and wherein the methodcomprises lowering HbA1c levels in the human subject by at least 0.3percentage points.
 3. The method of claim 1, wherein the administeringcomprises administering the insulin or the insulin analog orally,subcutaneously, or by injection.
 4. The method of claim 1, wherein the{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof is administered in asolid dosage form.
 5. The method of claim 4, wherein the solid dosageform is a tablet or capsule.
 6. The method of claim 4, wherein the soliddosage form comprises 400-450 mg of{2-[3-cyclohexyl-3-(trans-4-propoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-aceticacid or a pharmaceutically acceptable salt thereof.
 7. The method ofclaim 1, wherein the glycated hemoglobin is HbA1c.
 8. The method ofclaim 1, wherein the insulin analog is a rapid-acting insulin, regular-or short-acting insulin, intermediate-acting insulin, a long-actinginsulin, or a combination thereof.
 9. The method of claim 1, wherein theinsulin analog comprises a short-acting insulin, intermediate-actinginsulin, or a long-acting insulin.
 10. The method of claim 9, whereinthe insulin analog comprises a combination of an intermediate-actinginsulin and a long-acting insulin.
 11. The method of claim 1, whereinthe insulin analog is insulin lispro, insulin aspart, insulin glulisine,isophane insulin, insulin zinc, insulin glargine, insulin detemir, orany combination thereof.
 12. The method of claim 1, wherein an insulinanalog is administered, and the insulin analog is insulin lispro orinsulin aspart.
 13. The method of claim 1, wherein the incidence ofdiabetic ketosis events in the human subject is reduced.